MicroRNAs (miRNAs) are regulatory RNA molecules that control a large variety of cancer processes including proliferation/cell cycle, survival, metabolism and metastasis, and have led the charge in the non-coding RNA (ncRNA) revolution. My lab has shown that they regulate key cancer genes and that their mis-expression can be both informational AND causal in cancer. This presents a unique diagnostic and therapeutic (theranostic) opportunity to use miRNA-based strategies as effective cancer biomarkers AND therapeutics. My general strategy is a unique three-pronged approach that grows and harnesses the new discoveries in miRNAs, coupled with the expertise in mouse models and clinical capabilities at HIRM/BIDMC/DFHCC, including: a. Comprehensive discovery and functional validation in the miRNA space in cancer. Even though the vast majority of human transcripts are non-coding and the vast majority of disease associated SNP lie in the nc portion of the genome, we understand very little of their roles in human cells. Here we will discover the key miRNAs mis-expressed in human cancers and their microenvironment, and mine the miRNA and 3?UTR portions of the genome for novel cancer alleles. These will be functionally validated in cell line assays, patient derived organoid (PDO) and xenograft (PDX) animal models. b. Overcoming delivery barriers to cancer tissue and target engagement. While we have had some success in targeting these novel RNA-based molecules to cancer tissues, the current approaches are largely non-tissue specific and we propose a program to make this more effective, testing intratumoral and ex vivo delivery and to ultimately personalize targeting. c. Advancing miRNA-based medicine to the clinic. Here I propose to use the miRNA profiles of patient tumor tissue to guide personalized treatment options based on patient miRNA deficiencies, targeting immune checkpoints etc., even to design a personalized regimen of miRNA-based molecules for therapy, initially testing the idea in PDO and PDX models. In addition, I propose to capitalize on my proximity to the best physicians and Phase I clinical trials units to facilitate the translation of our preclinical work to clinical applications, in both diagnostic and therapeutic areas. I hope these novel, individualized methods will converge on standard of care for cancer patients in the future. While this approach could be relevant to many difficult-to-treat tumor types, I present my rationale for starting in PDAC and NSCLC, where I have been successful in collaborating with clinical investigators to apply our expertise here. While miRNA therapeutics are still a novel approach to broadly target cancer pathways, we are the first to propose miRNA screening with an eye towards personalized therapeutics and integrating miRNAs into standard of care for cancer patients. As the Director of the new Harvard Medical School Institute for RNA Medicine, I will pursue all of these goals as well as attempt to harness the resources (research /clinical /intellectual) of the Harvard community in these efforts, and hope to deliver these advancements to patients.